Another Look at Herpes Simplex

Chronic Flare-Ups Pose Harm to Brain

A virus that most of us carry but think little about should probably make us think twice, says Nancy Sawtell, PhD.

Sawtell, a researcher in the Division of Infectious Diseases, has been studying herpes simplex virus (HSV) for two decades. She, together with her collaborator Richard Thompson, PhD, at the University of Cincinnati College of Medicine, have discovered a number of things about the virus – and hope that what they have learned will change our largely cavalier attitude about it.

“This virus, which most of us have, has the potential to be wicked,” Sawtell says. “We have not done a good job educating people about it.” In fact, “wicked” might be an understatement. Once we contract HSV – and estimates are that between 70 and 90 percent of the world population has it – we can’t get rid of it. The virus remains latent in the nervous system for a lifetime, but periodically can flare up to cause anything from mild cold sores to genital rashes to encephalitis, blindness and even death. HSV may even have a link to Alzheimer’s disease, Sawtell says.

What Makes the Virus Reactivate

A year ago, Sawtell published her discovery that the viral protein VP 16 is essential in triggering the virus’s reactivation.

“VP 16 brings HSV out of latency and causes it to make lytic viral proteins,” she says. “This elicits an inflammatory response.”

Most of these episodes are relatively mild. Many people experience only minor symptoms like cold sores. Research also has shown that some people with active virus show no symptoms at all.

Medications such as acyclovir help shorten an outbreak, but they don’t attack the problem at its core, Sawtell says. “The virus still exits latency and creates an inflammatory response. Having something that blocks the virus before it enters the lytic cycle could help reduce chronic inflammation.”

Her team is working on an assay to screen for inhibitors of VP 16, which could lead to a treatment that would prevent the earliest stages of viral reactivation.

The Alzheimer's Connection

Sawtell wants to stop this lytic cycle because she has evidence that repeated inflammation caused by the virus harms the central nervous system.

“Having a latent virus that periodically reactivates in your central nervous system can’t be a good thing,” she says.

Sawtell is investigating whether repeated cycles of inflammation might lead to Alzheimer’s disease for some individuals. The idea was brought to her attention by British researcher Ruth Itzhaki, PhD.

“She had a hypothesis that carrying this chronic latent infection in your brain, when combined with a certain genetic background, represents a very high risk of developing Alzheimer’s,” Sawtell says.

By her own admission, Sawtell “was skeptical” about the idea. But Itzhaki’s research found that individuals who have a combination of latent HSV in the brain and the genetic variant APOE 4 have increased risk of acquiring Alzheimer’s disease. “And this work is fairly convincing” says Sawtell, “but demonstrating causality is difficult without an animal model.” So Sawtell began working with mice in which the human APOE 4 allele was knocked in, and infected them with HSV.

“A lot more virus got into the brains of the animals with the APOE 4 allele,” she says.

Sawtell also induced reactivation of the virus episodically over a long period of time to see what happened in the mouse’s central nervous system.

The Role of Genetics

Her next step will be to map the genes that regulate the phenotype in which the brain lesions appear, in an effort to determine what makes some people more susceptible.

“There are certainly groups of people who seem to be genetically predisposed to chronic inflammatory damage in their central nervous system as a result of acquiring HSV as kids,” she says.

For those people, she believes, this virus that has long been considered fairly benign is anything but.

“We are beginning to gain insight into the effects of long term latency in the brain,” Sawtell says. “If we died at 35 or 40 it wouldn’t make any difference. But we don’t, and our mental health is critically important as we live longer.”

Her ongoing HSV research will pursue two ultimate goals. “We need to protect our younger generation from becoming infected,” Sawtell says. “And we need to come up with strategies to protect against the exit from latency.”